MicroRNAs as Targets for the Treatment of Hepatocellular Carcinoma We have investigated the role of alterations in microRNA expression in hepatocellular carcinoma (HCC) and cirrhosis versus normal liver and whether alterations in the expression of unique microRNAs are associated with metastatic HCC and correlates with prognosis and recurrence. We have discovered microRNA expression signatures specific for hepatocellular carcinomas and for metastatic disease. In this project we propose to assess the role of alterations in several microRNAs in the pathogenesis of HCC to define microRNAs that are suitable targets for therapeutic intervention. We will focus on miR181a/b, miR21, miR25, miR221/222 and miR155 that are overexpressed in HCC and miR145, miR215, miR125, miR126, miR192, miR223, and miR122a, that are down-regulated in HCC. We also found microRNAs that potentially target the 3' UTR of the maintenance (DNMT1) and the de novo (DNMT3A, 3B) DNA methyltransferases. We will assess whether loss of these microRNAs result in overexpression of DNMTs and silencing of tumor suppressor genes associated to hepatocellular carcinogenesis. At the same time we will sequence the 3' UTRs of the DNA methyltransferases DNMT1, DNMT3A and 3B to determine whether mutations in target sequences of microRNAs result in their upregulation. Thus the proposed study intends to establish the role of alterations in microRNA expression in the initiation and progression of hepatocellular carcinoma and to validate microRNAs as targets for therapeutic intervention in hepatocellular carcinoma.